Pd-Catalyzed Cascade Reactions of Aziridines: One-Step Access to Complex Tetracyclic Amines

The combination of palladium catalysis and thermal cycloaddition is shown to transform tricyclic aziridines into complex, stereodefined tetracyclic products in a single step. This highly unusual cascade process involves a diverted Tsuji–Trost sequence leading to a surprisingly facile intramolecular Diels–Alder reaction. The starting materials are accessible on multigram scales from the photochemical rearrangement of simple pyrroles. The tetracyclic amine products can be further elaborated through routine transformations, highlighting their potential as scaffolds for medicinal chemistry.

Pd2(dba)3/PPh3 AcOH 100 a Added in an equimolar quantity to substrate; b Determined by 1 H NMR after 45 min at 70 °C; c A mixture of 13 and the corresponding acetamide was formed.
Preliminary experiments were undertaken to gain some insight into the mechanism of the key diene formation stage, using aziridine 2a. With the original catalyst, diene formation is rapid, both in the presence or absence of potassium carbonate (Entries 1 & 2). Use of Pd(PPh3)4 led to no detectable product within the same time period (Entry 3). Simple addition of AcOH led to rapid reaction (Entry 4), whereas the presence of Ph3P(O) did not (Entry 5). To explore this further, additional additives were investigated using Pd(PPh3)4. Ac2O reaction was complete after 45 min (Entry 6), CsOAc led to a slower conversion (29%, Entry 7), and acetate (Bu4NOAc) proved ineffective (Entry 8). Similar results were obtained using the Pd2(dba)3/PPh3 catalytic system, where using alone led to no observed reaction (Entry 9), addition of Ph3P(O) again failed to effect any reaction (Entry 10) and addition of AcOH led to rapid reaction. These results are consistent with N-activation being key to the observed reactivity, with this being achieved by protonation (AcOH), reaction with an electrophile (Ac2O) or complexation to a coordinating metal.  3.38 ± 0.02 × 10 -5 -10 100 3.98 ± 0.03 × 10 -5 -

General Considerations for Kinetic Experiments
Rate constants were obtained using 1 H-NMR spectroscopy, acquired on a 500 MHz Varian spectrometer. A solution of substrate and standard, 1,3,5-trimethoxybenzene, were dissolved in deuterated PhMe (0.7 mL) and a RT 1 H-NMR was obtained. The instrument was then heated to the required temperature, and another spectrum was obtained. Spectra were obtained every 20 minutes for between 12 to 20 hours and the 1 H-NMR array data was processed using MestReNova. Errors were calculated in Microsoft Excel via a least squares analysis.

Representative Kinetic Experiment
A standard solution of allylated diene 6aa (10.4 mg, 0.04 mmol), 1,3,5-trimethoxybenzene (1 mg, 0.006 mmol) in PhMe (0.7 mL) was added into an NMR tube, which was manually loaded into the NMR spectrometer with the probe temperature set at 25 °C. A spectrum was obtained at this temperature, then the probe was heated to 85 °C with the sample loaded within the magnet. The time taken to reach this temperature was recorded (generally ~15 mins for the instrument to reach temperature), and then an array of experiments was started, without further tuning or shimming, collecting spectra every 20 mins for 20 hours.

Methyl 2-(acetoxymethyl) acrylate 5b
To a stirred solution of methyl 2-(hydroxymethyl) acrylate (0.89 mL, 8.6 mmol), dry CH2Cl2 (18 mL) and pyridine at -10°C was added acetyl chloride (0.80 mL, 11 mmol) dropwise. The resulting solution was warmed to rt and stirred for 2 h. After this time the reaction was cooled to 0°C and water (30 mL) was charged. The aqueous layer was extracted with EtOAc (30 mL × 3) and the resulting organics washed with water (30 mL), sat. NH4Cl (30 mL) and brine (30 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified over silica gel (10 -30% EtOAc in petrol) to afford 5b (

2-(Hydroxymethyl)acrylonitrile S2
To a stirred solution of 37% aq. formaldehyde (5.5 mL, 74 mmol) and diethyl cyanomethylphosphonoacetate (3 mL, 19 mmol) was added saturated K2CO3 (4.0 mL, 32 mmol) dropwise over 30 min. The resulting solution was stirred at rt for 1.5 h. The reaction was quenched with NH4Cl (6 mL), the layers separated, and the aqueous layer extracted with Et2O (3 × 5 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified over silica gel (

2-Cyanoallyl acetate 5d
To a stirred solution of 2-(hydroxymethyl)acrylonitrile S2 (0.59 g, 7.1 mmol) in dry CH2Cl2 (12 mL) was added acetic anhydride (2.0 mL, 22 mmol), triethylamine (1.2 mL, 8.5 mmol) and DMAP (26 mg, 0.23 mmol). The resulting solution was stirred at rt for 20 h. The reaction was quenched with MeOH (2 mL) and stirred for 10 mins, followed by sat. aq. NaHCO3 (4 mL) and stirred for a further 10 min. The phases were allowed to settle and separated and the aqueous layer extracted with CH2Cl2 (2 × 6 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated to almost dryness in vacuo with low temperature and vacuum used to avoid evaporation of the volatile product. The crude product was purified over silica gel (10 -40% Et2O in pentane) to afford 5d (0.58 g, 66%) as a colourless oil. νmax/cm -